Generating tumor treating fields (TTFields) with high uniformity throughout the brain

ABSTRACT

This application discloses configurations for arranging transducer arrays on a person&#39;s head to impose tumor treating fields (TTFields) in the brain at field strengths that are as uniform as possible throughout the entire brain. In some embodiments, L-shaped sets of electrodes are positioned near the right and left ears, each with a horizontal arm above the ear and a vertical arm behind the ear. Optionally, these embodiments may be combined with a second pair of electrodes positioned on top of the head and behind the neck. In other embodiments, one pair of electrodes is positioned above the right ear and on the left/rear portion of the neck; and a second pair of electrodes is positioned above the left ear and on the right/rear portion of the neck. These configurations improve the uniformity of the electric fields imposed throughout the brain, and are particularly useful for preventing and/or treating metastases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.16/599,686, filed Oct. 11, 2019, which claims the benefit of U.S.Provisional Application 62/745,689 filed Oct. 15, 2018, each of which isincorporated herein by reference in its entirety.

BACKGROUND

TTFields are low intensity (e.g., 1-4 V/cm) alternating electric fieldswithin the intermediate frequency range (e.g., 100-300 kHz), which maybe used, for example, to treat tumors as described in U.S. Pat. No.7,565,205, which is incorporated herein by reference in its entirety.TTFields therapy is an approved mono-treatment for recurrentglioblastoma (GBM), and an approved combination therapy withchemotherapy for newly diagnosed GBM patients. The alternating electricfields are induced non-invasively by transducer arrays (i.e., arrays ofcapacitively coupled electrodes) placed directly on the patient's head(e.g., using the Novocure Optune® system), and applying AC voltagesbetween the transducer arrays.

For treating glioblastoma, the TTFields are delivered to patients viafour transducer arrays 11-14 that are placed on the patient's skin inclose proximity to a tumor (e.g., as depicted in FIGS. 1A-1D for aperson with glioblastoma). The transducer arrays 11-14 are arranged intwo pairs, and each transducer array is connected via a cable to an ACsignal generator. The AC signal generator (a) sends an AC currentthrough one pair of arrays 11, 12 during a first period of time, whichinduces an electric field with a first direction through the tumor; then(b) sends an AC current through the other pair of arrays 13, 14 during asecond period of time, which induces an electric field with a seconddirection through the tumor; then repeats steps (a) and (b) for theduration of the treatment.

In the context of glioblastoma, conventional solutions (e.g., NovoTALsoftware from Novocure) are available for determining where thetransducer arrays 11-14 should be placed on a subject's head in order tomaximize the field strength within the tumor. But because the prior artsolutions are only concerned with the field distribution within thetumor, none of the prior art solutions addressed the uniformity of theelectric field in other regions of the brain.

SUMMARY OF THE INVENTION

One aspect of the invention is directed to a first method of applying analternating electric field to a person's brain. The first methodcomprises affixing a first set of electrode elements to a right side ofthe person's head. The first set of electrode elements has an uppersection positioned above the external opening of the person's right earcanal with an orientation that is predominantly horizontal, and a rearsection positioned behind the external opening of the person's right earcanal with an orientation that is predominantly vertical. The firstmethod also comprises affixing a second set of electrode elements to aleft side of the person's head. The second set of electrode elements hasan upper section positioned above the external opening of the person'sleft ear canal with an orientation that is predominantly horizontal, anda rear section positioned behind the external opening of the person'sleft ear canal with an orientation that is predominantly vertical. Thefirst method also comprises applying an alternating voltage between thefirst set of electrode elements and the second set of electrodeelements. The applying is performed after affixing the first and secondsets of electrode elements to the person's head.

In some instances of the first method, the upper section of the firstset of electrode elements includes at least three capacitively coupledelectrode elements, the rear section of the first set of electrodeelements includes at least three capacitively coupled electrodeelements, the upper section of the second set of electrode elementsincludes at least three capacitively coupled electrode elements, and therear section of the second set of electrode elements includes at leastthree capacitively coupled electrode elements.

In some instances of the first method, the upper section of each of thefirst and second sets of electrode elements (a) has a length of at least6 cm, (b) is positioned less than 6 cm above the external opening of therespective ear canal, (c) has a front end positioned at least 1 cm infront of the external opening of the respective ear canal, and (d) has arear end positioned at least 1 cm behind the external opening of therespective ear canal.

In some instances of the first method, the rear section of each of thefirst and second sets of electrode elements (a) has a length of at least6 cm, (b) is positioned less than 6 cm behind the external opening ofthe respective ear canal, (c) has an upper end positioned at least 1 cmabove the external opening of the respective ear canal, and (d) has arear end positioned at least 3 cm below the external opening of therespective ear canal.

In some instances of the first method, the upper section of the firstset of electrode elements includes at least three capacitively coupledelectrode elements, the rear section of the first set of electrodeelements includes at least three capacitively coupled electrodeelements, the upper section of the second set of electrode elementsincludes at least three capacitively coupled electrode elements, and therear section of the second set of electrode elements includes at leastthree capacitively coupled electrode elements; the upper section of eachof the first and second sets of electrode elements (a) has a length ofat least 6 cm, (b) is positioned less than 6 cm above the externalopening of the respective ear canal, (c) has a front end positioned atleast 1 cm in front of the external opening of the respective ear canal,and (d) has a rear end positioned at least 1 cm behind the externalopening of the respective ear canal; and the rear section of each of thefirst and second sets of electrode elements (a) has a length of at least6 cm, (b) is positioned less than 6 cm behind the external opening ofthe respective ear canal, (c) has an upper end positioned at least 1 cmabove the external opening of the respective ear canal, and (d) has arear end positioned at least 3 cm below the external opening of therespective ear canal.

Some instances of the first method further comprise affixing a third setof electrode elements having a third centroid to the person's head withthe third centroid positioned on top of the person's head; affixing afourth set of electrode elements having a fourth centroid to the back ofthe person's neck with the fourth centroid positioned below the person'sC2 vertebra and above the person's C7 vertebra; and applying analternating voltage between the third set of electrode elements and thefourth set of electrode elements, wherein the applying is performedafter affixing the third and fourth sets of electrode elements to theperson's head. The steps of (a) applying an alternating voltage betweenthe first set of electrode elements and the second set of electrodeelements and (b) applying an alternating voltage between the third setof electrode elements and the fourth set of electrode elements arerepeated in an alternating sequence. In these instances, the third setof electrode elements may optionally be affixed with the third centroidpositioned between 1 and 3 cm anterior to a vertex of the person's head.In these instances, the fourth set of electrode elements may optionallybe affixed with the fourth centroid positioned below the person's C3vertebra and above the person's C6 vertebra. In these instances, thethird set of electrode elements may optionally be affixed with the thirdcentroid positioned between 1 and 3 cm anterior to a vertex of theperson's head, while the fourth set of electrode elements is affixedwith the fourth centroid positioned below the person's C3 vertebra andabove the person's C6 vertebra.

In some instances of the first method, the specific locations at whichthe first and second sets of electrode elements are affixed to the rightand left sides of the person's head, respectively, are determined byrunning finite element simulations for an individual person to calculatea resulting electric field for each combination of positions for thefirst and second sets of electrode elements; and selecting thecombination of positions for the first and second sets of electrodeelements that results in the lowest value of Ψ, where Ψ=σT÷MEANT,σ_(T)=SD([μ_(i)]|i∈{α, β, γ, δ, in}), and MEAN_(T)=mean([μ_(i)]|i∈{α, β,γ, δ, in}).

In some instances of the first method, the alternating voltage has afrequency between 100 and 300 kHz.

Another aspect of the invention is directed to a second method ofapplying an alternating electric field to a brain in a person's body,the body having a mid-coronal plane and a mid-sagittal plane. The secondmethod comprises affixing a first set of electrode elements to theperson's head on a right side of the mid-sagittal plane, superior to theexternal opening of the person's right ear canal; affixing a second setof electrode elements having a second centroid to the person's body on aleft side of the mid-sagittal plane and behind the mid-coronal plane,with the second centroid positioned inferior to an external opening ofthe person's left ear canal, and superior to the person's C7 vertebra;affixing a third set of electrode elements to the person's head on aleft side of the mid-sagittal plane, superior to the external opening ofthe person's left ear canal; and affixing a fourth set of electrodeelements having a fourth centroid to the person's body on a right sideof the mid-sagittal plane and behind the mid-coronal plane, with thefourth centroid positioned inferior to an external opening of theperson's right ear canal, and superior to the person's C7 vertebra. Thesecond method also comprises repeating, in an alternating sequence (a)applying an alternating voltage between the first set of electrodeelements and the second set of electrode elements, and (b) applying analternating voltage between the third set of electrode elements and thefourth set of electrode elements. In the second method, the repeating isperformed after affixing the first, second, third, and fourth sets ofelectrode elements.

In some instances of the second method, the second centroid and thefourth centroid are positioned superior to a midpoint of the person's C2vertebra. In some instances of the second method, the second centroidand the fourth centroid are positioned inferior to a midpoint of theperson's C2 vertebra. In some instances of the second method, the secondcentroid and the fourth centroid are positioned inferior to the person'sC3 vertebra and superior to the person's C6 vertebra.

In some instances of the second method, the specific locations at whichthe first, second, third, and fourth sets of electrode elements areaffixed to the person's body are determined by running finite elementsimulations for an individual person to calculate a resulting electricfield for each combination of positions for the first, second, third,and fourth sets of electrode elements; and selecting the combination ofpositions for the first, second, third, and fourth sets of electrodeelements that results in the lowest value of Ψ, where Ψ=σT÷MEAN_(T),σ_(T)=SD([μ_(i)]|i∈{α, β, γ, δ, in}), and MEAN_(T)=mean([μ_(i)]|i∈{α, β,γ, δ, in}).

In some instances of the second method, the alternating voltage has afrequency between 100 and 300 kHz.

Another aspect of the invention is directed to a first apparatus. Thefirst apparatus comprises a flexible backing having an outer side and aninner side, wherein the flexible backing is configured for affixation toa side of a person's head with the inner side facing the person's head.The flexible backing has a first arm with a length of at least 6 cm in afirst direction and a second arm with a length of at least 6 cm in asecond direction, wherein the second direction is between 65° and 115°away from the first direction. The first apparatus also comprises afirst plurality of capacitively coupled electrode elements positioned onthe inner side of the first arm of the flexible backing, wherein each ofthe first plurality of capacitively coupled electrode elements has aconductive plate with a dielectric layer disposed thereon that facesinward; and a second plurality of capacitively coupled electrodeelements positioned on the inner side of the second arm of the flexiblebacking, wherein each of the second plurality of capacitively coupledelectrode elements has a conductive plate with a dielectric layerdisposed thereon that faces inward. The first apparatus also comprises afirst set of conductors that connects to the conductive plates of eachof the first plurality of capacitively coupled electrode elements; and asecond set of conductors that connects to the conductive plates of eachof the second plurality of capacitively coupled electrode elements. Thefirst apparatus also comprises a layer of adhesive positioned to holdportions of the flexible backing that are not covered by any of theelectrode elements against the person's head.

In some embodiments of the first apparatus, the first plurality ofcapacitively coupled electrode elements comprises at least threecapacitively coupled electrode elements, and the second plurality ofcapacitively coupled electrode elements comprises at least threecapacitively coupled electrode elements. In some embodiments of thefirst apparatus, the second direction is between 80° and 100° away fromthe first direction. In some embodiments of the first apparatus, thesecond direction is 90° away from the first direction. In someembodiments of the first apparatus, the first plurality of capacitivelycoupled electrode elements are all wired together in parallel. In someembodiments of the first apparatus, the second plurality of capacitivelycoupled electrode elements are all wired together in parallel.

Another aspect of the invention is directed to a third method ofdetermining where to position a set of electrode elements on a person'shead before the set of electrodes is used to apply an alternatingelectric field to the person's brain. The third method comprises (a)simulating affixation of a first set of electrode elements to a rightside of the person's head at a first plurality of positions, the firstset of electrode elements having an upper section positioned above theexternal opening of the person's right ear canal with an orientationthat is predominantly horizontal, and a rear section positioned behindthe external opening of the person's right ear canal with an orientationthat is predominantly vertical. The third method also comprises (b)simulating affixation of a second set of electrode elements to a leftside of the person's head at a second plurality of positions, the secondset of electrode elements having an upper section positioned above theexternal opening of the person's left ear canal with an orientation thatis predominantly horizontal, and a rear section positioned behind theexternal opening of the person's left ear canal with an orientation thatis predominantly vertical. The third method also comprises (c)simulating application of an alternating voltage between the first setof electrode elements and the second set of electrode elements at eachof the first plurality of positions and at each of the second pluralityof positions, respectively. The third method also comprises (d)determining, based on step (c), which of the first plurality ofpositions and which of the second plurality of positions results in analternating electric field in the person's brain with high uniformity.The third method also comprises (e) outputting, based on a result ofstep (d), a recommended position for the first set of electrode elementsand a recommended position for the second set of electrode elements.

In some instances of the third method, the upper section of each of thefirst and second sets of electrode elements (a) has a length of at least6 cm, (b) is positioned less than 6 cm above the external opening of therespective ear canal, (c) has a front end positioned at least 1 cm infront of the external opening of the respective ear canal, and (d) has arear end positioned at least 1 cm behind the external opening of therespective ear canal.

In some instances of the third method, the rear section of each of thefirst and second sets of electrode elements (a) has a length of at least6 cm, (b) is positioned less than 6 cm behind the external opening ofthe respective ear canal, (c) has an upper end positioned at least 1 cmabove the external opening of the respective ear canal, and (d) has arear end positioned at least 3 cm below the external opening of therespective ear canal.

Some instances of the third method further comprise (g) simulatingaffixation of a third set of electrode elements having a third centroidto the person's head at a third plurality of positions with the thirdcentroid positioned on top of the person's head; (h) simulatingaffixation of a fourth set of electrode elements having a fourthcentroid to the back of the person's neck at a fourth plurality ofpositions with the fourth centroid positioned below the person's C2vertebra and above the person's C7 vertebra; (i) simulating applicationof an alternating voltage between the third set of electrode elementsand the fourth set of electrode elements at each of the third pluralityof positions and at each of the fourth plurality of positions,respectively; (j) determining which of the third plurality of positionsand which of the fourth plurality of positions results in an alternatingelectric field in the person's brain with high uniformity; and (k)outputting, based on a result of step (j), a recommended position forthe third set of electrode elements and a recommended position for thefourth set of electrode elements.

In some instances of the third method that include steps (g) through(j), the simulated affixation has the third set of electrode elementsaffixed with the third centroid positioned between 1 and 3 cm anteriorto a vertex of the person's head. In some instances of the third methodthat include steps (g) through (j), the simulated affixation has thefourth set of electrode elements affixed with the fourth centroidpositioned below the person's C3 vertebra and above the person's C6vertebra.

In some instances of the third method that include steps (g) through(j), the simulated affixation has the third set of electrode elementsaffixed with the third centroid positioned between 1 and 3 cm anteriorto a vertex of the person's head, and the simulated affixation has thefourth set of electrode elements affixed with the fourth centroidpositioned below the person's C3 vertebra and above the person's C6vertebra.

In some instances of the third method, step (d) comprises selecting thecombination of positions for the first and second sets of electrodeelements that results in the lowest value of Ψ, where Ψ=σT÷MEANT,σ_(T)=SD([μ_(i)]|i∈{α, β, γ, δ, in}), and MEAN_(T)=mean([μ_(i)]|i∈{α, β,γ, δ, in}).

Another aspect of the invention is directed to a fourth method ofdetermining where to position a set of electrode elements on a person'sbody before the set of electrodes is used to apply an alternatingelectric field to a brain in the person's body. The body has amid-coronal plane and a mid-sagittal plane. The fourth method comprises(a) simulating affixation of a first set of electrode elements to theperson's head at a first plurality of positions on a right side of themid-sagittal plane, superior to the external opening of the person'sright ear canal. The fourth method also comprises (b) simulatingaffixation of a second set of electrode elements having a secondcentroid to the person's body at a second plurality of positions on aleft side of the mid-sagittal plane and behind the mid-coronal plane,with the second centroid positioned inferior to an external opening ofthe person's left ear canal, and superior to the person's C7 vertebra.The fourth method also comprises (c) simulating affixation of a thirdset of electrode elements to the person's head at a third plurality ofpositions on a left side of the mid-sagittal plane, superior to theexternal opening of the person's left ear canal. The fourth method alsocomprises (d) simulating affixation of a fourth set of electrodeelements having a fourth centroid to the person's body at a fourthplurality of positions on a right side of the mid-sagittal plane andbehind the mid-coronal plane, with the fourth centroid positionedinferior to an external opening of the person's right ear canal, andsuperior to the person's C7 vertebra. The fourth method also comprises(e) simulating application of an alternating voltage between the firstset of electrode elements and the second set of electrode elements ateach of the first plurality of positions and at each of the secondplurality of positions, respectively. The fourth method also comprises(f) simulating application of an alternating voltage between the thirdset of electrode elements and the fourth set of electrode elements ateach of the third plurality of positions and at each of the fourthplurality of positions, respectively. The fourth method also comprises(g) determining, based on steps (e) and (f), which of the firstplurality of positions, which of the second plurality of positions,which of the third plurality of positions, and which of the fourthplurality of positions results in an alternating electric field in theperson's brain with high uniformity. And the fourth method alsocomprises (h) outputting, based on a result of step (g), a recommendedposition for the first set of electrode elements, a recommended positionfor the second set of electrode elements, a recommended position for thethird set of electrode elements, and a recommended position for thefourth set of electrode elements.

In some instances of the fourth method, the simulated affixation has thesecond centroid and the fourth centroid positioned superior to amidpoint of the person's C2 vertebra.

In some instances of the fourth method, the simulated affixation has thesecond centroid and the fourth centroid positioned inferior to amidpoint of the person's C2 vertebra.

In some instances of the fourth method, the simulated affixation has thesecond centroid and the fourth centroid positioned inferior to theperson's C3 vertebra and superior to the person's C6 vertebra.

In some instances of the fourth method, step (g) comprises selecting thecombination of positions for the first, second, third, and fourth setsof electrode elements that results in the lowest value of Ψ, whereΨ=σT÷MEANT, σ_(T)=SD([μ_(i)]|i∈{α, β, γ, δ, in}), andMEAN_(T)=mean([μ_(i)]|i∈{α, β, γ, δ, in}).

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D depict the conventional layout for positioning transducerarrays on a person's head for treating glioblastoma using TTFields.

FIGS. 2A-2D depict a set of improved layouts for positioning transducerarrays on a person's head for preventing metastases using TTFields.

FIGS. 3A-3D depict another set of improved layouts for positioningtransducer arrays on a person's head for preventing metastases usingTTFields.

FIGS. 4A-4D depict yet another set of improved layouts for positioningtransducer arrays on a person's head for preventing metastases usingTTFields.

FIG. 5 depicts a block diagram of a system that may be used to apply theAC voltage across the sets of electrode elements depicted in FIGS. 2, 3,and 4 .

FIGS. 6A and 6B depict how the brain is divided into five distinctregions α, β, γ, δ, and in.

FIG. 7 depicts an apparatus that may be used for each of the sets ofelectrode elements shown in FIGS. 4A and 4B.

Various embodiments are described in detail below with reference to theaccompanying drawings, wherein like reference numerals represent likeelements.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Many types of cancer (e.g., lung, breast, colon, kidney and melanoma)can metastasize to the brain. TTFields can be used to treat and preventmetastases, as described in U.S. Pat. No. 7,599,746.

Because one never knows in advance the exact location within the brainthat a metastasis may appear, a good way to prevent or treat metastasesis to treat as much of the brain as possible with TTFields. Keeping thefield strength as uniform as possible within the entire brain canmaximize the percentage of the brain that receives a field strengthlarge enough to prevent or treat the metastases, while preventing thetransducer arrays from getting too hot and also conserving batterypower. Consistent with these objectives, this application discloses avariety of configurations for arranging the transducer arrays on aperson's head to impose TTFields in the brain at field strengths thatare as uniform as possible throughout the entire brain (including theinfratentorial regions of the brain).

FIGS. 1A-1D depict the conventional layout for positioning transducerarrays on a person's head for treating glioblastoma using TTFields. Withthis layout, the AC signal generator first applies an AC voltage acrossthe front/back pair of transducer arrays 11, 12, then applies an ACvoltage across the right/left pair of transducer arrays 13, 14, and thenrepeats that two-step sequence for the duration of the treatment. Astabulated below, the uniformity of field intensity for this conventionallayout is relatively low. One of the main reasons for the low uniformityis that the field strengths are quite low in the infratentorial regionsof the brain.

FIGS. 2A-2D depict one set of improved layouts for positioningtransducer arrays on a person's head for preventing metastases usingTTFields. More specifically, FIG. 2A shows that the first set ofelectrode elements 21 is affixed to a person's head on a right side ofthe mid-sagittal plane, superior to the external opening of the person'sright ear canal; FIG. 2B shows that the second set of electrode elements22 is affixed to the person's body on a left side of the mid-sagittalplane and behind the mid-coronal plane, with its centroid positionedinferior to an external opening of the person's left ear canal, andsuperior to the midpoint of the person's C2 vertebra; FIG. 2C shows thatthe third set of electrode elements 23 is affixed to the person's headon a left side of the mid-sagittal plane, superior to the externalopening of the person's left ear canal; and FIG. 2D shows that thefourth set of electrode elements 24 is affixed to the person's body on aright side of the mid-sagittal plane and behind the mid-coronal plane,with its centroid positioned inferior to an external opening of theperson's right ear canal, and superior to the midpoint of the person'sC2 vertebra. With this layout, the AC signal generator first applies anAC voltage across the first and second sets of electrode elements 21,22, then applies an AC voltage across the third and fourth sets ofelectrode elements 23, 24, and then repeats that two-step sequence forthe duration of the treatment. As tabulated below, the uniformity offield intensity for this alternative layout is significantly higher thanin the conventional FIG. 1 layout.

FIGS. 3A-3D depict another set of improved layouts for positioningtransducer arrays on a person's head for preventing metastases usingTTFields. This layout is similar to the FIG. 2A-2D layout, except thatthe second and fourth sets of electrode elements 32, 34 are positionedlower down on the person's body. More specifically, FIG. 3A shows thatthe first set of electrode elements 31 is affixed to a person's head ona right side of the mid-sagittal plane, superior to the external openingof the person's right ear canal; FIG. 3B shows that the second set ofelectrode elements 32 is affixed to the person's body on a left side ofthe mid-sagittal plane and behind the mid-coronal plane, with itscentroid positioned inferior to the midpoint of the person's C2 vertebraand superior to the person's C7 vertebra; FIG. 3C shows that the thirdset of electrode elements 33 is affixed to the person's head on a leftside of the mid-sagittal plane, superior to the external opening of theperson's left ear canal; and FIG. 3D shows that the fourth set ofelectrode elements 34 is affixed to the person's body on a right side ofthe mid-sagittal plane and behind the mid-coronal plane, with itscentroid positioned inferior to the midpoint of the person's C2 vertebraand superior to the person's C7 vertebra. With this layout, the ACsignal generator first applies an AC voltage across the first and secondsets of electrode elements 31, 32, then applies an AC voltage across thethird and fourth sets of electrode elements 33, 34, and then repeatsthat two-step sequence for the duration of the treatment. As tabulatedbelow, the uniformity of field intensity for this alternative layout isalso significantly higher than in the conventional FIG. 1 layout.

FIGS. 4A-4D depict yet another set of improved layouts for positioningtransducer arrays on a person's head for preventing metastases usingTTFields. More specifically, FIG. 4A shows that the first set ofelectrode elements 41 is affixed to a right side of the person's head.The first set of electrode elements 41 has an upper section 41Hpositioned above (i.e., superior to) the external opening of theperson's right ear canal with an orientation that is predominantlyhorizontal, and a rear section 41V positioned behind the externalopening of the person's right ear canal with an orientation that ispredominantly vertical. FIG. 4B shows that the second set of electrodeelements 42 is affixed to a left side of the person's head. The secondset of electrode elements has an upper section 42H positioned above theexternal opening of the person's left ear canal with an orientation thatis predominantly horizontal, and a rear section 42V positioned behindthe external opening of the person's left ear canal with an orientationthat is predominantly vertical. FIGS. 4C and 4D show that the third setof electrode elements 43 is affixed to the person's head with itscentroid positioned on top of the person's head; and FIG. 4D shows thatthe fourth set of electrode elements 44 is affixed to the back of theperson's neck with its centroid positioned below the person's C2vertebra and above the person's C7 vertebra. With this layout, the ACsignal generator first applies an AC voltage across the first and secondsets of electrode elements 41, 42, then applies an AC voltage across thethird and fourth sets of electrode elements 43, 44, and then repeatsthat two-step sequence for the duration of the treatment. As tabulatedbelow, the uniformity of field intensity for this alternative layout isalso significantly higher than in the conventional FIG. 1 layout.

Optionally, in the FIGS. 4A-4D layout, the upper section 41H of thefirst set of electrode elements includes at least three capacitivelycoupled electrode elements, the rear section 41V of the first set ofelectrode elements includes at least three capacitively coupledelectrode elements, the upper section 42H of the second set of electrodeelements includes at least three capacitively coupled electrodeelements, and the rear section 42V of the second set of electrodeelements includes at least three capacitively coupled electrodeelements. In alternative embodiments, each of those sections 41H, 41V,42H, 42V can include a different number of electrode elements (e.g.,between 1 and 8).

Optionally, in the FIGS. 4A-4D layout, the upper section of each of thefirst and second sets of electrode elements (a) has a length of at least6 cm, (b) is positioned less than 6 cm above the external opening of therespective ear canal, (c) has a front end positioned at least 1 cm infront of the external opening of the respective ear canal, and (d) has arear end positioned at least 1 cm behind the external opening of therespective ear canal.

Optionally, in the FIGS. 4A-4D layout, the rear section of each of thefirst and second sets of electrode elements (a) has a length of at least6 cm, (b) is positioned less than 6 cm behind the external opening ofthe respective ear canal, (c) has an upper end positioned at least 1 cmabove the external opening of the respective ear canal, and (d) has alower end positioned at least 3 cm below the external opening of therespective ear canal.

Optionally, in the FIGS. 4A-4D layout, the third set of electrodeelements is affixed with its centroid positioned between 1 and 3 cmanterior to a vertex of the person's head.

Optionally, in the FIGS. 4A-4D layout, the fourth set of electrodeelements is affixed with its centroid positioned below the person's C3vertebra and above the person's C6 vertebra.

FIG. 5 depicts a block diagram of a system that includes an AC voltagegenerator 50 that may be used to apply the AC voltage across the firstand second sets of electrode elements (21/22, 31/32, and 41/42 in FIGS.2, 3, and 4 , respectively) and across the third and fourth sets ofelectrode elements (23/24, 33/34, and 43/44 in FIGS. 2, 3, and 4 ,respectively) in an alternating sequence as described above inconnection with FIGS. 2-4 above.

For each of the transducer array layouts depicted above, electric fieldswere simulated using a realistic human head model extending as far asthe shoulders. In the simulations, transducer arrays with 9 capacitivelycoupled disc-shaped electrode elements, each having a diameter of 2 cm,were placed on the locations on the body described above in connectionwith FIGS. 1-4 , and a constant current of 2 A peak-to-peak with a 200kHz frequency was applied to the outer surfaces of the disks. Thesimulations were performed using Sim4Life version 4 platform(ZMT-Zurich). To analyze the uniformity of the electric field, the brainwas divided into five compartments as depicted in FIGS. 6A-6B: theinfratentorial areas “in” (including the cerebellum and brain stem), andfour compartments for the upper brain—front-right α, front-left β,rear-left γ, and rear-right δ. The boundaries between these regions ofthe brain are depicted in FIGS. 6A-6B. The field intensity wascalculated for each voxel in each of the five compartments using finiteelement simulation. For each compartment the mean and median fieldintensities of all voxels in the compartment were calculated. Data wastaken only for grey and white matter cells.

For each pair of transducer arrays in each of the layouts depictedabove, w was defined as the standard deviation between the mean of thedifferent compartments divided by the average of the differentcompartments, as follows.

$\Psi = \frac{\sigma_{T}}{{MEAN}_{T}}$where σ_(T)=SD([μ_(i)]|i∈{α, β, γ, δ, in});and MEAN_(T)=mean([μ_(i)]|i∈{α, β, γ, δ, in})

In these three equations, SD stands for standard deviation; μi is themean of each compartment; α, β, γ and δ are the cerebral compartments(see FIG. 6A); and “in” is the cerebellum/brain stem compartment (seeFIG. 6B).

The value of Ψ obtained (in percent) for each individual pair oftransducer arrays are presented in Table 1 below.

TABLE 1 FIGS. 1A/1B 1C/1D 2A/2B 2C/2D 3A/3B 3C/3D 4A/4B 4C/4D Electrodes11/12 13/14 21/22 23/24 31/32 33/34 41/42 43/44 Ψ [%] 29.38* 29.38 17.1920.16 27.25 28.8 15.55 15.48 *The value for the FIGS. 1A-1B layout wasestimated.

Based on the results in Table 1, when only a single pair of transducerarrays is used to impose a field in a person's brain, the two bestlayouts for positioning the transducer arrays to obtain the highestuniformity throughout the brain are the layouts 43/44 (depicted in FIGS.4C/4D); and the layouts 41/42 (depicted in FIGS. 4A/4B).

Next, for each set of the transducer array layouts depicted in FIGS. 1-4, the uniformity of the field created throughout the brain was evaluatedby using finite element simulation to calculate the field strength ateach voxel in the brain in the following two situations: (a) when an ACvoltage is applied across the first and second sets of electrodeelements (11/12, 21/22, 31/32, and 41/42, in FIGS. 1, 2, 3, and 4 ,respectively), and (b) when an AC voltage is applied across the thirdand fourth sets of electrode elements (13/14, 23/24, 33/34, and 43/44,in FIGS. 1, 2, 3, and 4 , respectively). Then, for each voxel in thebrain, the field strength result for situation (a) and the fieldstrength result for situation (b) were averaged.

After obtaining the average field strength at each voxel in the brain, Ψwas calculated using the same three equations that were used tocalculate Ψ described above in connection with Table 1. Except thistime, instead of using a single field strength for each voxel in thebrain as the input to the equations, an average of two field strengthsfor each voxel in the brain was used as the input to the equations.

The value of Ψ obtained for each set of four transducer arrays (inpercent) are presented in Table 2 below. These values are based on theassumption that the field is applied between the first and secondtransducer arrays in any given set half the time, and between the thirdand fourth transducer arrays in the given set the other half of thetime.

TABLE 2 FIGS. 1A-1D 2A-2D 3A-3D 4A-4D Electrode pairs that 11/12 and21/22 and 31/32 and 41/42 and were averaged 13/14 23/24 33/34 43/44 Ψ[%] 29.38* 5.23 8.21 3.03 *The result for the FIGS. 1A-1D layout relieson the estimate identified above in connection with Table 1.

Based on the results in Table 2, when two pairs of transducer arrays areused to impose a field in a person's brain, with each pair beingenergized 50% of the time in an alternating sequence, the two bestlayouts for positioning the transducer arrays to obtain the highestuniformity throughout the brain are (1) the layouts 41/42 combined with43/44 (as depicted in FIGS. 4A-4D); and (2) the layouts 21/22 combinedwith 23/24 (as depicted in FIGS. 2A-2D).

Additional data for the transducer array layouts depicted above in FIGS.2-4 are provided below. For the positioning of the transducer arrays21/22 depicted in FIGS. 2A/2B, the data was as shown below in Table 3.

TABLE 3 α β γ δ in Mean intensity (V/cm) 2.02 1.83 1.23 1.76 1.69 Medianintensity (V/cm) 2.03 1.81 1.22 1.64 1.66 % volume over 1 V/cm 98.1198.70 80.76 95.47 95.78 Standard Deviation 0.52 0.42 0.25 0.60 0.40

For the positioning of the transducer arrays 23/24 depicted in FIGS.2C/2D the data was as shown below in Table 4.

TABLE 4 α β γ δ in Mean intensity (V/cm) 1.15 1.64 2.05 1.87 1.69 Medianintensity (V/cm) 1.14 1.49 2.06 1.86 1.68 % volume over 1 V/cm 71.1590.76 98.34 98.92 93.51 Standard Deviation 0.24 0.59 0.53 0.41 0.44

For the positioning of the transducer arrays 31/32 depicted in FIGS.3A/3B, the data was as shown below in Table 5.

TABLE 5 α β γ δ in Mean intensity (V/cm) 2.20 1.73 1.20 1.15 1.62 Medianintensity (V/cm) 2.22 1.69 1.17 1.11 1.61 % volume over 1 V/cm 98.4697.12 74.30 68.44 97.55 Standard Deviation 0.60 0.44 0.29 0.28 0.30

For the positioning of the transducer arrays 33/34 depicted in FIGS.3C/3D the data was as shown below in Table 6.

TABLE 6 α β γ δ in Mean intensity (V/cm) 1.12 1.07 2.13 1.71 1.58 Medianintensity (V/cm) 1.08 1.03 2.13 1.68 1.58 % volume over 1 V/cm 64.5556.06 98.48 95.83 96.07 Standard Deviation 0.29 0.28 0.57 0.46 0.32

For the positioning of the transducer arrays 41/42 depicted in FIGS.4A/4B, the data was as shown below in Table 7.

TABLE 7 α β γ δ in Mean intensity (V/cm) 1.16 1.57 1.28 1.65 1.65 Medianintensity (V/cm) 1.16 1.52 1.31 1.64 1.72 % volume over 1 V/cm 70.2686.89 76.03 91.69 94.10 Standard Deviation 0.32 0.50 0.37 0.47 0.39

For the positioning of the transducer arrays 43/44 depicted in FIGS.4C/4D the data was as shown below in Table 8.

TABLE 8 α β γ δ in Mean intensity (V/cm) 1.94 1.48 2.01 1.47 1.56 Medianintensity (V/cm) 1.89 1.44 1.99 1.43 1.53 % volume over 1 V/cm 98.7094.82 98.58 94.47 97.00 Standard Deviation 0.54 0.34 0.57 0.35 0.32

In the embodiments depicted in FIGS. 2, 3, and 4C/4D, each set ofelectrode elements is configured as a 3×3 array of individual electrodeelement discs. As a result, in these embodiments, the centroid of therespective set will coincide with the center of the center disc. But inalternative embodiments, each set of electrode elements may include adifferent number of electrode elements. For example, a given set ofelectrode elements may be configured as a 2×2 array of individualelectrode element discs. In this situation, the centroid could be in aregion that is located between all four disks. In other alternativeembodiments, a given set of electrode elements may include only a singleelectrode element disc (which may be any suitable shape including butnot limited to round and rectangular). In this situation, the centroidwould coincide with the center of that single electrode element.

In the embodiments depicted in FIGS. 2-5 , all four sets of electrodeelements are preferably capacitively coupled to the person's body. Afteraffixing the first, second, third, and fourth sets of electrode elementsas described above for the respective embodiments, the following stepsare repeated in an alternating sequence: (a) applying an alternatingvoltage between the first set of electrode elements and the second setof electrode elements, and (b) applying an alternating voltage betweenthe third set of electrode elements and the fourth set of electrodeelements. In some embodiments, the frequency of these alternatingvoltages is between 100 kHz and 300 kHz.

For the embodiments described above in connection with FIGS. 2-5 , thevalues provided in Tables 1-7 were obtained by simulating the electricfields that are obtained when each of the four sets of electrodeelements was positioned as depicted in FIGS. 2-4 . Note, however, thatthe positions of each set of electrode elements may be varied from theexact locations depicted in those figures, as long as the movement issmall enough so that the respective anatomic description above remainsunchanged. For example, the first set of electrode elements 21 depictedin FIG. 2A can move up, down, or to either side, as long as it remainsaffixed to a person's head on a right side of the mid-sagittal plane,superior to the external opening of the person's right ear canal.Similarly, the second set of electrode elements 22 depicted in FIG. 2Bcan move up, down, or to either side, as long as it remains affixed tothe person's body on a left side of the mid-sagittal plane and behindthe mid-coronal plane, with its centroid positioned inferior to anexternal opening of the person's left ear canal, and superior to themidpoint of the person's C2 vertebra. Within this limited range ofmovement, the optimum position of each of the four sets of electrodeelements may be determined using simulations (e.g., finite elementsimulations) for each individual person to calculate the resultingelectric field for each combination of positions for the various sets ofelectrodes, and selecting the combination that provides the best results(e.g., the highest uniformity of the field throughout the brain, or thesmallest Ψ). An indication of the selected combination is then output tothe care provider using, for example, a suitable display or printout.The care provider will then apply the sets of electrode elements to theperson at the positions indicated by the output, hook the sets ofelectrode elements up to the AC signal generator 50, and commencetreatment.

FIG. 7 depicts an apparatus that may be used to implement either thefirst set of electrode elements 41 that is affixed to the right side ofthe person's head (shown in FIG. 4A) or the second set of electrodeelements 42 that is affixed to the left side of the person's head (shownin FIG. 4B).

This apparatus is used for applying an alternating electric field to aperson's brain, and it comprises a flexible backing 70 having an outerside 76 (hidden in FIG. 7 ) and an inner side 75. The flexible backing70 is configured for affixation to a side of the person's head with theinner side 75 facing the person's head. Suitable materials for theflexible backing include cloth, foam, and flexible plastic (e.g.,similar to corresponding materials used in bandages). The flexiblebacking has a first arm 71 with a length of at least 6 cm in a firstdirection d1 and a second arm with a length of at least 6 cm in a seconddirection d2.

A first plurality of capacitively coupled electrode elements 81 ispositioned on the inner side 75 of the first arm 71 of the flexiblebacking 70, and each of the first plurality of capacitively coupledelectrode elements 81 has a conductive plate 81 c with a dielectriclayer disposed thereon that faces inward. A second plurality ofcapacitively coupled electrode elements 82 is positioned on the innerside 75 of the second arm 72 of the flexible backing 70, and each of thesecond plurality of capacitively coupled electrode elements 82 has aconductive plate 82 c with a dielectric layer disposed thereon thatfaces inward. The electrode elements 81, 82 may be similar to theconventional electrode elements used in the Novocure Optune® system.Optionally, temperature sensors (e.g., thermistors) may be positionedbeneath some or all of the electrode elements 81, 82 in a manner that issimilar to the conventional arrangement used in the Novocure Optune®system.

A first set of conductors 61 connects to the conductive plates 81 c ofeach of the first plurality of capacitively coupled electrode elements81 in parallel, and a second set of conductors 62 connects to theconductive plates 82 c of each of the second plurality of capacitivelycoupled electrode elements 82 in parallel. The conductors 62 may beimplemented using, for example, discrete wiring or using traces on aflex circuit. A layer of adhesive (indicated by the dotted pattern) ispositioned on the inner side 75 of the flexible backing 70, and thisadhesive is configured to hold portions of the flexible backing 70 thatare not covered by any of the electrode elements 81, 82 against theperson's head.

In the embodiment depicted in FIG. 7 , the first plurality of electrodeelements 81 has four electrode elements and the second plurality ofelectrode elements 82 has three electrode elements. However, inalternative embodiments, the number of electrode elements in each of thefirst and second pluralities of electrode elements can vary (e.g.,between 2 and 10).

In the embodiment depicted in FIG. 7 , the angle θ between the firstdirection d1 and the second direction d2 is 90°. However, in alternativeembodiments, that angle θ can be between 80° and 100°, or between 65°and 115°.

Note that in the orientation depicted in FIG. 7 , the apparatus issuited for use as the second set of electrodes 42 that is positionednext to the left ear in FIG. 4B, with the first and second pluralitiesof electrode elements 81, 82 in FIG. 7 corresponding to theupper/horizontal arm 42H and the rear/vertical arm 42V, respectively, inFIG. 4B. But if the backing 70 is rotated clockwise by 90° with respectto the orientation shown in FIG. 7 , the same apparatus would then besuited for use as the first set of electrodes 41 that is positioned nextto the right ear in FIG. 4A. More specifically, after a 90° clockwiserotation, the first plurality of electrode elements 81 in FIG. 7 wouldcorrespond to the rear/vertical arm 41V in FIG. 4A, and the secondplurality of electrode elements 82 in FIG. 7 would correspond to theupper/horizontal arm 41H in FIG. 4A.

While the present invention has been disclosed with reference to certainembodiments, numerous modifications, alterations, and changes to thedescribed embodiments are possible without departing from the sphere andscope of the present invention, as defined in the appended claims.Accordingly, it is intended that the present invention not be limited tothe described embodiments, but that it has the full scope defined by thelanguage of the following claims, and equivalents thereof.

What is claimed is:
 1. A method of applying an alternating electricfield to a person's brain, the method comprising: affixing a first setof electrode elements to a right side of the person's head, the firstset of electrode elements having an upper section positioned above theexternal opening of the person's right ear canal with an orientationthat is predominantly horizontal, and a rear section positioned behindthe external opening of the person's right ear canal with an orientationthat is predominantly vertical, wherein at least a portion of the rearsection of the first set of electrode elements is positioned below theexternal opening of the person's right ear canal, and wherein at least aportion of the upper section of the first set of electrode elements ispositioned in front of the external opening of the person's right earcanal; affixing a second set of electrode elements to a left side of theperson's head, the second set of electrode elements having an uppersection positioned above the external opening of the person's left earcanal with an orientation that is predominantly horizontal, and a rearsection positioned behind the external opening of the person's left earcanal with an orientation that is predominantly vertical, wherein atleast a portion of the rear section of the second set of electrodeelements is positioned below the external opening of the person's leftear canal, and wherein at least a portion of the upper section of thesecond set of electrode elements is positioned in front of the externalopening of the person's left ear canal; and applying an alternatingvoltage between the first set of electrode elements and the second setof electrode elements, wherein the applying is performed after affixingthe first and second sets of electrode elements to the person's head. 2.The method of claim 1, wherein the upper section of the first set ofelectrode elements includes at least three capacitively coupledelectrode elements, the rear section of the first set of electrodeelements includes at least three capacitively coupled electrodeelements, the upper section of the second set of electrode elementsincludes at least three capacitively coupled electrode elements, and therear section of the second set of electrode elements includes at leastthree capacitively coupled electrode elements.
 3. The method of claim 1,wherein the upper section of each of the first and second sets ofelectrode elements (a) has a length of at least 6 cm, (b) is positionedless than 6 cm above the external opening of the respective ear canal,(c) has a front end positioned at least 1 cm in front of the externalopening of the respective ear canal, and (d) has a rear end positionedat least 1 cm behind the external opening of the respective ear canal.4. The method of claim 1, wherein the rear section of each of the firstand second sets of electrode elements (a) has a length of at least 6 cm,(b) is positioned less than 6 cm behind the external opening of therespective ear canal, (c) has an upper end positioned at least 1 cmabove the external opening of the respective ear canal, and (d) has alower end positioned at least 3 cm below the external opening of therespective ear canal.
 5. The method of claim 1, further comprising:affixing a third set of electrode elements having a third centroid tothe person's head with the third centroid positioned on top of theperson's head; affixing a fourth set of electrode elements having afourth centroid to the back of the person's neck with the fourthcentroid positioned below the person's C2 vertebra and above theperson's C7 vertebra; and applying an alternating voltage between thethird set of electrode elements and the fourth set of electrodeelements, wherein the applying is performed after affixing the third andfourth sets of electrode elements to the person's head, wherein thesteps of (a) applying an alternating voltage between the first set ofelectrode elements and the second set of electrode elements and (b)applying an alternating voltage between the third set of electrodeelements and the fourth set of electrode elements are repeated in analternating sequence.
 6. The method of claim 5, wherein the third set ofelectrode elements is affixed with the third centroid positioned between1 and 3 cm anterior to a vertex of the person's head, and wherein thefourth set of electrode elements is affixed with the fourth centroidpositioned below the person's C3 vertebra and above the person's C6vertebra.
 7. The method of claim 6, wherein the upper section of thefirst set of electrode elements includes at least three capacitivelycoupled electrode elements, the rear section of the first set ofelectrode elements includes at least three capacitively coupledelectrode elements, the upper section of the second set of electrodeelements includes at least three capacitively coupled electrodeelements, and the rear section of the second set of electrode elementsincludes at least three capacitively coupled electrode elements, whereinthe upper section of each of the first and second sets of electrodeelements (a) has a length of at least 6 cm, (b) is positioned less than6 cm above the external opening of the respective ear canal, (c) has afront end positioned at least 1 cm in front of the external opening ofthe respective ear canal, and (d) has a rear end positioned at least 1cm behind the external opening of the respective ear canal, and whereinthe rear section of each of the first and second sets of electrodeelements (a) has a length of at least 6 cm, (b) is positioned less than6 cm behind the external opening of the respective ear canal, (c) has anupper end positioned at least 1 cm above the external opening of therespective ear canal, and (d) has a lower end positioned at least 3 cmbelow the external opening of the respective ear canal.
 8. The method ofclaim 1, wherein the specific locations at which the first and secondsets of electrode elements are affixed to the right and left sides ofthe person's head, respectively, are determined by running finiteelement simulations for an individual person to calculate a resultingelectric field for each combination of positions for the first andsecond sets of electrode elements, and selecting the combination ofpositions for the first and second sets of electrode elements thatresults in the lowest value of Ψ, where Ψ=σ_(T)÷MEAN_(T), where σ_(T) isthe standard deviation between the mean field intensity of the differentcompartments, MEANT_(T) is the average field intensity of the differentcompartments, σ_(T)=SD([μ_(i)]|i∈{α, β, γ, δ, in}), where SD is thestandard deviation, μ_(i) is the mean of each compartment i for thecerebral compartments α, β, γ, δ, and “in”, where “in” is thecerebellum/brain stem compartment, and MEAN_(T)=mean([μ_(i)]|i∈{α, β, γ,δ, in}).
 9. The method of claim 1, wherein the alternating voltage has afrequency between 100 and 300 kHz.
 10. A method of determining where toposition a set of electrode elements on a person's head before the setof electrodes is used to apply an alternating electric field to theperson's brain, the method comprising: (a) simulating affixation of afirst set of electrode elements to a right side of the person's head ata first plurality of positions, the first set of electrode elementshaving an upper section positioned above the external opening of theperson's right ear canal with an orientation that is predominantlyhorizontal, and a rear section positioned behind the external opening ofthe person's right ear canal with an orientation that is predominantlyvertical, wherein at least a portion of the rear section of the firstset of electrode elements is positioned below the external opening ofthe person's right ear canal, and wherein at least a portion of theupper section of the first set of electrode elements is positioned infront of the external opening of the person's right ear canal; (b)simulating affixation of a second set of electrode elements to a leftside of the person's head at a second plurality of positions, the secondset of electrode elements having an upper section positioned above theexternal opening of the person's left ear canal with an orientation thatis predominantly horizontal, and a rear section positioned behind theexternal opening of the person's left ear canal with an orientation thatis predominantly vertical, wherein at least a portion of the rearsection of the second set of electrode elements is positioned below theexternal opening of the person's left ear canal, and wherein at least aportion of the upper section of the second set of electrode elements ispositioned in front of the external opening of the person's left earcanal; (c) simulating application of an alternating voltage between thefirst set of electrode elements and the second set of electrode elementsat each of the first plurality of positions and at each of the secondplurality of positions, respectively; (d) determining, based on step(c), which of the first plurality of positions and which of the secondplurality of positions results in an alternating electric field in theperson's brain with high uniformity; and (e) outputting, based on aresult of step (d), a recommended position for the first set ofelectrode elements and a recommended position for the second set ofelectrode elements.
 11. The method of claim 10, wherein the uppersection of each of the first and second sets of electrode elements (a)has a length of at least 6 cm, (b) is positioned less than 6 cm abovethe external opening of the respective ear canal, (c) has a front endpositioned at least 1 cm in front of the external opening of therespective ear canal, and (d) has a rear end positioned at least 1 cmbehind the external opening of the respective ear canal.
 12. The methodof claim 10, wherein the rear section of each of the first and secondsets of electrode elements (a) has a length of at least 6 cm, (b) ispositioned less than 6 cm behind the external opening of the respectiveear canal, (c) has an upper end positioned at least 1 cm above theexternal opening of the respective ear canal, and (d) has a lower endpositioned at least 3 cm below the external opening of the respectiveear canal.
 13. The method of claim 10, further comprising: (g)simulating affixation of a third set of electrode elements having athird centroid to the person's head at a third plurality of positionswith the third centroid positioned on top of the person's head; (h)simulating affixation of a fourth set of electrode elements having afourth centroid to the back of the person's neck at a fourth pluralityof positions with the fourth centroid positioned below the person's C2vertebra and above the person's C7 vertebra; (i) simulating applicationof an alternating voltage between the third set of electrode elementsand the fourth set of electrode elements at each of the third pluralityof positions and at each of the fourth plurality of positions,respectively; (j) determining which of the third plurality of positionsand which of the fourth plurality of positions results in an alternatingelectric field in the person's brain with high uniformity; and (k)outputting, based on a result of step (j), a recommended position forthe third set of electrode elements and a recommended position for thefourth set of electrode elements.
 14. The method of claim 10, whereinstep (d) comprises selecting the combination of positions for the firstand second sets of electrode elements that results in the lowest valueof Ψ, where Ψ=σ_(T)÷MEAN_(T), where σ_(T) is the standard deviationbetween the mean field intensity of the different compartments,MEANT_(T) is the average field intensity of the different compartments,σ_(T)=SD([μ_(i)]|i∈{α, β, γ, δ, in}), where SD is the standarddeviation, μ_(i) is the mean of each compartment i for the cerebralcompartments α, β, γ, δ, and “in”, where “in” is the cerebellum/brainstem compartment, and MEAN_(T)=mean([μ_(i)]|i∈{α, β, γ, δ, in}).